The present invention relates to new arylsulfonamides and analogues, processes for their preparation and their use for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy and craniocerebral trauma.
xcex949-Tetrahydrocannabinol (xcex949-THC) and, to a small extent, also xcex948-THC are the biologically active constituents in extracts of the plant Cannabis sativa (marihuana, hashish) and are responsible for the effects on the human central nervous system (CNS). Potential historical and contemporary therapeutic uses of cannabis preparations include, inter alia, analgesia, emesis, anorexia, glaucoma and mobility disorders.
Until now, two subtypes of cannabinoid receptors and a splice variant have been identified. The CB1 receptor (Nature 1990, 346, 561) and a splice variant CB1a (J. Biol. Chem. 1995, 270, 3726) are mainly localized in the central nervous system. The CB2 receptor was mainly found in the peripheral tissue, in particular in leucocytes, spleen and macrophages (Eur. J. Biochem. 1995, 232, 54).
CB1 and CB2 receptors have seven transmembrane regions and belong to the family of G protein receptors. Both receptors are negatively coupled via Gi/Goprotein to adenylate cyclase and possibly negatively coupled to the presynaptic release of glutamates (J. Neurosci. 1996, 16, 4322). CB1 receptors are moreover positively coupled to potassium channels and also negatively coupled to N- and Q-type calcium channels.
Four classes of CB1 receptor agonists are known to date; classical cannabinoids, such as, for example, xcex949-THC, non-classical cannabinoids, aminoalkylindoles and eicosanoids. The latter include the generally accepted endogenous CB1 receptor agonist anandamide.
It is additionally known that cerebral apoplexy is a consequence of a sudden circulatory disorder of a human brain region with subsequent functional losses, with corresponding neurological and/or physiological symptoms. The causes of cerebral apoplexy can lie in cerebral haemorrhages (e.g. after a vascular tear in hypertension, arteriosclerosis and aneurysms) and ischaemia (e.g due to a blood pressure fall crisis or embolism). The functional losses in the brain lead to a degeneration or destruction of the brain cells (Journal of Cerebral Blood Flow and Metabolism 1981, 1, 155; Chem. Eng. News 1996 (May 13), 41; Trends Pharmacol. Sci. 1996, 17, 227)). Cranial cerebral trauma is understood as meaning covered and open cranial injuries with involvement of the brain
The present invention relates to compounds of the general formula (I)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94R2xe2x80x83xe2x80x83(I)
in which
R1 represents (C6-C10)-aryl, quinolyl, isoquinolyl or a radical of the formula 
in which
a denotes a number 1 or 2,
R3 denotes hydrogen, (C2-C6)-alkenyl, (C1-C6)-alkyl or (C1-C6)-acyl, and where all the abovementioned ring systems and radicals are optionally substituted, if appropriate geminally, by one or more, identical or different substituents which are selected from the group which consists of:
halogen, carboxyl, hydroxyl, phenyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C1-C8)-alkyl, which, for its part, can be substituted by halogen, (C1-C6)-alkylsulphonyloxy, azide, amino, mono(C1-C6)-alkylamino, di(C1-C6)-alkylamino or hydroxyl,
a group of the formula xe2x80x94(CO)bxe2x80x94NR4R5,
in which
b denotes a number 0 or 1,
R4 and R5 are identical or different and independently of one another denote hydrogen, phenyl, (C1-C6)-acyl, cyclo(C4-C7)-acyl, benzoyl or (C1-C6)-alkyl which is optionally substituted by amino, mono(C1-C6)-alkylamino, di(C1-C6)-alkylamino,
or
R4 and R5, together with the nitrogen atom, form a 5- or -membered saturated heterocycle which can optionally contain one or more further heteroatoms from the group consisting of S and O and/or one or more radicals of the formula xe2x80x94NR8,
in which
R8 denotes hydrogen, (C1-C6)-alkyl or (C1-C6)-acyl,
and
a group of the formula xe2x80x94NR6xe2x80x94SO2xe2x80x94R7 
in which
R6 denotes hydrogen, phenyl, (C1-C6)-alkyl or (C1-C6)-acyl,
R7 denotes phenyl or (C1-C6)-alkyl,
A and E are identical or different and represent a bond or (C1-C4)-alkylene,
D represents an oxygen atom or a radical of the formula xe2x80x94S(O)cxe2x80x94 or xe2x80x94N(R9)xe2x80x94,
in which
c denotes a number 0, 1 or 2,
R9 denotes hydrogen, (C1-C6)-alkyl or (C1-C6)-acyl,
G represents doubly bonded (C6-C10)-aryl or a doubly bonded 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
hydroxyl, trifluoromethyl, carboxyl, halogen, (C1-C6)-alkyl, hydroxy(C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl,
and also groups of the formulae
xe2x80x94COxe2x80x94Oxe2x80x94(CH2)dxe2x80x94NR10xe2x80x94R11, xe2x80x94NR12xe2x80x94SO2R13,
xe2x80x94(CH2)exe2x80x94(CO)fxe2x80x94NR14R15 and xe2x80x94OR16,
in which
d denotes a number 1, 2, 3 or 4,
e and f are identical or different and denote a number 0 or 1,
R10 and R11 have the meaning of R4 and R5 indicated above and are identical to or different from this,
R12 has the meaning of R6 indicated above and is identical to or different from this,
R13 has the meaning of R7 indicated above and is identical to or different from this,
R14 and R15 have the meaning of R4 and R5 indicated above and are identical to or different from this,
or independently of one another represents a radical of the formula
xe2x80x94(CH2)gxe2x80x94NR17R18,
in which
g denotes a number 1, 2, 3 or 4,
and
R17 and R18 have the meaning of R4 and R5 indicated above and are identical to or different from this,
R16 denotes (C6-C10)-aryl,
L represents a radical of the formula
xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94,

where the bonding of the radicals to G takes place at the left bond,
and in which R19, R20, R21, R22, R23, R24, R25, R26 and R27 are identical or different and denote hydrogen or (C1-C4)-alkyl,
or
R19 denotes a radical of the formula xe2x80x94SO2R2,
R2 represents (C6-C10)-aryl or a 5- to 7-membered saturated or aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, trifluoromethyl, nitro, amino and (C1-C6)-alkyl,
or
represents the radical of the formula 
or morpholine, or
represents C3-C8-cycloalkyl, or
represents (C1-C12)-alkyl, (C2-C12)-alkenyl or (C2-C12)-alkinyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, trifluoromethyl, hydroxyl, cyano, azido, (C1-C6)-alkoxy, (C1-C6)-perfluoroalkoxy, partially fluorinated (C1-C6)-alkoxy, a radical of the formula 
in which R28 and R29 have the meaning of R4 and R5 indicated above and are identical to or different from this,
phenyl, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, nitro, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy and a group of the formula xe2x80x94NR30R31,
in which R30 and R31 are identical or different and denote hydrogen or (C1-C6)-alkyl or (C1-C6)-acyl,
and a 5- to 6-membered aromatic heterocycle having up to three heteroatoms from the group consisting of S, N and/or O, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, nitro, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy and a group of the formula xe2x80x94NR30R31,
in which R30 and R31 are as defined above,
or
L and R2 together represent a radical of the formula 
and their salts.
Preferred compounds of the formula (I) are those in which
R1 represents phenyl, naphthyl, quinolyl, isoquinolyl or a radical of the formula 
in which
a denotes a number 1 or 2,
R3 denotes hydrogen. (C2-C4)-alkenyl, (C1-C4)-alkyl or (C1-C4)-acyl,
and where all the abovementioned ring systems and radicals are optionally substituted, if appropriate geminally, by one or more, identical or different substituents which are selected from the group which consists of:
halogen, carboxyl, hydroxyl, phenyl, (C1-C4)-alkoxy, (C1-C5)-alkoxycarbonyl, (C1-C6)-alkyl which, for its part, can be substituted by halogen, (C1-C4)-alkylsulphonyloxy, azide, amino, mono(C1-C4)-alkylamino, di(C1-C4)-alkylamino or hydroxyl,
a group of the formula xe2x80x94(CO)bxe2x80x94NR4R5 
in which
b denotes a number 0 or 1,
R4 and R5 are identical or different and independently of one another denote hydrogen, phenyl, (C1-C4)-acyl, cyclo(C4-C7)-acyl, benzoyl or (C1-C4)-alkyl which is optionally substituted by amino, mono(C1-C4)-alkylamino, di(C1-C4)-alkyl,
or
R4 and R5, together with the nitrogen atom, form a morpholine, piperidine or N-methylpiperazine ring,
and
a group of the formula xe2x80x94NR6xe2x80x94SO2xe2x80x94R7 
in which
R6 denotes hydrogen, phenyl, (C1-C4)-alkyl or (C1-C4)-acyl
and
R7 denotes phenyl or (C1-C5)-alkyl,
A and E are identical or different and represent a bond or (C1-C4)-alkylene,
D represents an oxygen atom or a radical of the formula xe2x80x94S(O)cxe2x80x94 or xe2x80x94NR9xe2x80x94,
in which
c denotes a number 0, 1 or 2,
R9 denotes hydrogen or (C1-C4)-alkyl or (C1-C4)-acyl,
G represents doubly bonded phenyl, naphthyl, pyrimidyl, pyridazinyl or pyridyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
hydroxyl, trifluoromethyl, carboxyl, halogen, (C1-C4)-alkyl, hydroxy(C1-C4)alkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxycarbonyl, and also groups of the formulae
xe2x80x94COxe2x80x94Oxe2x80x94(CH2)dxe2x80x94NR10R11, xe2x80x94NR12xe2x80x94SO2R13,
xe2x80x94(CH2)exe2x80x94(CO)fxe2x80x94NR14R15 and xe2x80x94OR16,
in which
d denotes a number 1, 2, 3 or 4,
e and f are identical or different and denote a number 0 or 1,
R10 and R11 have the meaning of R4 and R5 indicated above and are identical to or different from this,
R12 has the meaning of R6 indicated above and is identical to or different from this,
R13 has the meaning of R7 indicated above and is identical to or different from this,
R14 and R15 have the meaning of R4 and R5 indicated above and are identical to or different from this, or independently of one another represent a radical of the formula
xe2x80x94(CH2)gxe2x80x94NR17R18,
in which
g denotes a number 1, 2 or 3,
and
R17 and R18 have the meaning of R10 and R11 indicated above and are identical to or different from this,
R16 denotes phenyl or naphthyl,
L represents a radical of the formula 
where the bonding of the radicals to G takes place at the left bond,
and
in which
R19, R20, R21, R22, R23, R24, R25, R26 and R27 are identical or different and denote hydrogen or (C1-C3)-alkyl,
or
R19 denotes a radical of the formula xe2x80x94SO2R2,
R2 represents phenyl, naphthyl, pyridyl, furyl, thienyl or pyrimidyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, amino, trifluoromethyl, nitro and (C1-C4)-alkyl,
or
represents the radical of the formula 
or morpholine,
or
represents cyclopropyl, cyclohexyl or cyclopentyl, or
represents (C1-C10)-alkyl, (C2-C10)-alkenyl or (C2-C10)-alkinyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, trifluoromethyl, hydroxyl, azido, (C1-C4)-alkoxy, (C1-C5)-perfluoroalkoxy, partially fluorinated (C1-C4)-alkoxy, a radical of the formula 
in which
R28 and R29 have the meaning of R4 and R5 indicated above and are identical to or different from this,
phenyl, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, nitro, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkoxy and a group of the formula xe2x80x94NR30R31,
in which R30 and R31 are identical or different and denote hydrogen or (C1-C4)-alkyl or (C1-C4)-acyl,
pyridyl and pyrimidyl, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
halogen, nitro, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkoxy and a group of the formula xe2x80x94NR30R31,
in which R30 and R31 are as defined above,
or
L and R2 together represent a radical of the formula 
and their salts
Particularly preferred compounds of the formula (I) are those in which
R1 represents phenyl, naphthyl, quinolyl, isoquinolyl or a radical of the formula 
in which
a denotes a number 1 or 2,
R3 denotes hydrogen, (C2-C3)-alkenyl, (C1-C3)-alkyl or (C1-C3)-acyl,
and where all the abovementioned ring systems are optionally substituted, if appropriate geminally, by one or more, identical or different substituents which are selected from the group which consists of:
chlorine, fluorine, carboxyl, hydroxyl, phenyl, (C1-C3)-alkoxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkyl which, for its part, can be substituted by chlorine, methylsulphonyloxy or hydroxyl,
a group of the formula xe2x80x94(CO)bxe2x80x94NR4R5 
in which
b denotes a number 0 or 1,
R4 and R5 are identical or different and independently of one another denote hydrogen, (C1-C3)-acyl, cyclo(C4-C6)-acyl, benzoyl or (C1-C3)-alkyl which is optionally substituted by amino, mono(C1-C3)-alkylamino, di(C1-C3)-alkyl amino,
or
R4 and R5, together with the nitrogen atom, form a morpholine, piperidine or N-methylpiperazine ring,
and
a group of the formula xe2x80x94NR6xe2x80x94SO2xe2x80x94R7 
in which
R6 denotes hydrogen, (C1-C3)-alkyl or (C1-C3)-acyl
and
R7 denotes phenyl or (C1-C4)-alkyl,
A and E are identical or different and represent a bond or (C1-C3)-alkyl,
D represents an oxygen atom or a radical of the formula xe2x80x94S(O)cxe2x80x94 or xe2x80x94NR9xe2x80x94,
in which
c denotes a number 0, 1 or 2,
R9 denotes hydrogen or (C1-C3)-alkyl or (C1-C3)-acyl,
G represents doubly bonded phenyl, naphthyl, pyrimidyl, pyridazinyl or pyridyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
hydroxyl, trifluoromethyl, carboxyl, fluorine, chlorine, bromine, (C1-C3)-alkyl, hydroxy(C1-C3)alkyl, (C1-C3)-alkoxy, (C1-C3)-alkoxycarbonyl, and also groups of the formulae
xe2x80x94COxe2x80x94Oxe2x80x94(CH2)dxe2x80x94NR10R11, xe2x80x94NR12xe2x80x94SO2R13,
xe2x80x94(CH2)exe2x80x94(CO)fxe2x80x94NR14R15, xe2x80x94CH2OH and xe2x80x94OR16,
in which
d denotes a number 1, 2 or 3,
e and f are identical or different and denote a number 0 or 1,
R10 and R11 denote hydrogen or methyl,
R12 denotes hydrogen,
R13 denotes (C1-C4)-alkyl,
R14 and R15 have the meaning of R4 and R5 indicated above and are identical to or different from this, or denote a radical of the formula xe2x80x94(CH2)gxe2x80x94NR17R18,
in which
g denotes a number 1, 2 or 3,
and
R17 and R18 denote hydrogen or methyl,
or
R14 and R15, together with the nitrogen atom, form a radical of the formula 
R16 denotes phenyl or naphthyl,
L represents a radical of the formula 
where the bonding of the radicals to G takes place at the left bond,
and
in which
R19, R20, R21, R22, R23, R24, R25, R26 and R27 are identical or different and denote hydrogen, methyl or ethyl,
or
R19 denote a radical of the formula xe2x80x94SO2R2,
R2 represents phenyl, furyl or pyridyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of: fluorine, chlorine, bromine or trifluoromethyl,
or
represents the radical of the formula 
or morpholine,
or
represents cyclopentyl or cyclohexyl, or
represents (C1-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-alkinyl, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, azido, (C1-C3)-alkoxy, (C1-C4)-perfluoroalkoxy, trifluoromethyl-substituted (C1-C4)-alkoxy, a radical of the formula 
in which
R28 and R29 denote hydrogen or methyl,
phenyl, pyridyl and pyrimidyl, optionally substituted by one or more, identical or different substituents which are selected from the group which consists of:
fluorine, chlorine, bromine, nitro, hydroxyl, (C1-C3)-alkyl, (C1-C3)-alkoxy and a group of the formula xe2x80x94NR30R31,
in which R30 and R31 are identical or different and denote hydrogen, methyl or methylcarbonyl,
or
L and R2 together represent a radical of the formula 
and their salts
The present invention also relates to compounds of the formula (I)
in which
R1 represents (C6-C10)-aryl, quinolyl or a radical of the formula 
in which
a denotes a number 1 or 2,
and where all the abovementioned ring systems and radicals are optionally substituted, if appropriate geminally, by 1 to 3 identical or different substituents which are selected from the group which consists of:
halogen, carboxyl, hydroxyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C1-C8)-alkyl which, for its parts, can be substituted by halogen or hydroxyl,
a group of the formula xe2x80x94(CO)bxe2x80x94NR4R5 
in which
b denotes a number 0 or 1,
R4 and R5 are identical or different and denote hydrogen, phenyl or (C1-C6)-alkyl,
and
a group of the formula xe2x80x94NR6xe2x80x94SO2xe2x80x94R7 
in which
R6 denotes hydrogen, phenyl or (C1-C6)-alkyl,
R7 denotes phenyl or (C1-C6)-alkyl,
A and E are identical or different and represent a bond or (C1-C4)-alkylene,
D represents an oxygen atom or a radical of the formula xe2x80x94S(O)cxe2x80x94 or xe2x80x94NHxe2x80x94,
in which
c denotes a number 0, 1 or 2,
G represents doubly bonded (C6-C10)-aryl or a double bonded 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, each of which is optionally substituted by up to three identical or different substituents which are selected from the group which consists of:
hydroxyl, carboxyl, halogen, (C1-C6)-alkyl, hydroxy(C1-C6)alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, and also groups of the formulae
xe2x80x94COxe2x80x94Oxe2x80x94(CH2)dxe2x80x94NR10R11, xe2x80x94NR12xe2x80x94SO2R13 and xe2x80x94COxe2x80x94NR14R15
in which
d denotes a number 1, 2, 3 or 4,
R10 and R11 have the meaning of R4 and R5 indicated above and are identical to or different from this,
R12 has the meaning of R6 indicated above and is identical to or different from this,
R13 has the meaning of R7 indicated above and is identical to or different from this,
R14 and R15 have the meaning of R4 and R5 indicated above and are identical to or different from this, or together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which can optionally additionally contain a further heteroatom from the group consisting of S and O or a group of the formula xe2x80x94NHxe2x80x94,
L represents a radical of the formula 
where the bonding, of the radicals to G takes place at the left bond,
and in which R19, R20, R21, R22, R23 and R24 are identical or different and denote hydrogen or (C1-C4)-alkyl,
R2 represents phenyl which is optionally substituted by halogen, trifluoromethyl, nitro, amino or (C1-C6)-alkyl,
R2 represents the radical of the formula 
or morpholine,
or
represents perfluoroalkyl having up to 12 fluorine atoms,
or
represents (C1-C12)-alkyl or (C2-C12)-alkinyl, each of which is optionally substituted by halogen, trifluoromethyl, hydroxyl, azido or by a radical of the formula 
in which R28 and R29 have the meaning of R4 and R5 indicated above and are identical to or different from this,
and/or are optionally substituted by phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, which, for their part, can be substituted up to 2 times identically or differently by halogen, nitro, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy or by a group of the formula xe2x80x94NR30R31,
in which R30 and R31 are identical or different and denote hydrogen, (C1-C6)-alkyl or (C1-C6)-acyl,
L and R2 together represent a radical of the formula 
and their salts.
Very particularly preferred compounds of the formula (I) according to the invention are those
in which
R1 represents naphth-1-yl, optionally substituted by (C1-C6)-alkyl substituted by hydroxyl, (C1-C6)-acylamino, amino or (C1-C6)-alkoxy, indan-4-yl, substituted by hydroxy(C1-C6)-alkyl,
a radical of the formula 
in which
R3 is (C1-C6)-alkyl,
E and A represent a bond,
D represents an oxygen atom,
G represents 1,3-phenylene, 1,4-phenylene or 2,5-pyridylene, each of which is optionally substituted by halogen,
L represents a radical of the formula xe2x80x94NHxe2x80x94SO2xe2x80x94 or xe2x80x94Oxe2x80x94SO2xe2x80x94 and
R2 represents (C1-C6)-alkyl which is optionally substituted by chlorine, trifluoromethyl, by a radical of the formula xe2x80x94Oxe2x80x94CH2xe2x80x94CF3 or by phenyl or by pyridyl, which for their part can be substituted by bromine or chlorine,
and their salts
In particular, the following very particularly preferred compounds may be mentioned: 
The compounds according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The present invention also includes ammonium compounds which can be prepared by conversion of the free amines by means of alkylation.
In the context of the present invention, the substituents in general have the following meaning:
(C1-C12)-Alkyl in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.
(C1-C8)-Alkyl having 1 to 8 carbon atoms, e.g. nonyl, decyl, undecyl, dodecyl, is preferred.
(C2-C12)-Alkenyl in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 2 to 6 and 2 to 20 carbon atoms and one or more, preferably having one or two, double bonds. The lower alkyl radical having 2 to 4 and 2 to 10 carbon atoms and a double bond is preferred. An alkenyl radical having 2 to 3 and 2 to 8 carbon atoms and a double bond is particularly preferred. Examples which may be mentioned are allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.
(C2-C12)-Alkinyl in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 2 to 12 carbon atoms and one or more, preferably having one or two, triple bonds. The lower alkyl radical having 2 to approximately 10 carbon atoms and a triple bond is preferred. An alkyl radical having 2 to 8 carbon atoms and a triple bond is particularly preferred. Examples which may be mentioned are acetylene, 2-butine, 2-pentine and 2-hexine.
(C1-C6)-Acyl in general represents, depending on the abovementioned substituents, straight-chain or branched lower alkyl having 1 to 6 carbon atoms which are bonded via a carbonyl group. Alkyl radicals having up to 4 carbon atoms are preferred. Alkyl radicals having up to 3 carbon atoms, for example, are very particularly preferred. Examples which may be mentioned are: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
(C1-C6)-Alkoxy in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical bonded via an oxygen atom and having 1 to 6 carbon atoms. Lower alkoxy having 1 to 4 carbon atoms is preferred. An alkoxy radical having 1 to 3 carbon atoms is particularly preferred. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.
(C1-C6)-Alkoxycarbonyl can be represented, for example, by the formula 
Alkyl here represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Lower alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety is preferred. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
(C3-C8)-Cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Cyclo(C4-C7)-acyl in general represents, depending on the abovementioned substituents, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl.
(C6-C10)-Aryl in general represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
(C1-C6)-Perfluoroalkoxy in the context of the invention represents an alkoxy radical having 1 to 6 carbon atoms and 3 to 13 fluorine atoms. An alkoxy radical having 1 to 5 carbon atoms and 3 to 9 fluorine atoms is preferred.
(C1-C6)-Partially fluorinated alkoxy in the context of the invention represents an alkoxy radical having 1 to 6 carbon atoms and 3 to 5 fluorine atoms. An alkoxy radical having 1 to 4 carbon atoms and 3 fluorine atoms is preferred. An alkoxy radical having 1 to 3 carbon atoms and which is substituted by trifluoromethyl is particularly preferred.
Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
Aromatic, saturated and unsaturated heterocycles in the context of the invention, depending on the abovementioned substituents, in general represent a 5- to 7-membered or 5- to 6-membered, preferably 5- to 6-membered, heterocycle which can contain up to 3 heteroatoms from the group consisting of S, N and/or O and which can optionally also be bonded via a nitrogen atom. Examples which may be mentioned are: pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, pyrimidyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Pyridyl, furyl, morpholinyl, piperidyl and piperazinyl are preferred.
Leaving groups in the sense of the invention are groups which can be replaced by a nucleophile in a nucleophilic substitution (Streitwieser, A., Jr.; Heathcock, C. H. Organische Chemie, Verlag Chemie, 1980, p. 169ff). Preferred leaving groups are halides and sulphonic acid esters/anhydrides. A particularly preferred leaving group is chloride.
(C3-C6)-Ketone in the context of the invention represents a saturated or unsaturated ketone having 3 to 6 carbon atoms. Examples which may be mentioned are: acetone, butanone, but-1-en-3-one, but-1-in-3-one, pentan-3-one, pentan-2-one, pent-1-en-3-one, pent-1-in-3-one, penta-1,4-dien-3-one, 3-methylbutan-2-one, cyclopropyl methyl ketone, cyclopentanone, hexan-2-one, hexan-3-one, cyclohexanone, 2-methylcyclopentanone, 2-ethylcyclobutanone.
(C1-C6)-Aldehyde in the context of the invention represents a saturated or unsaturated aldehyde having 1 to 6 carbon atoms. Examples which may be mentioned are: formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, cyclopropylcarbaldehyde, but-2-enal, but-2-inal, pentanal, isopentanal, pivaldehyde, cyclobutylcarbaldehyde, 2-methylcyclopropylcarbaldehyde, pent-2-enal, pent-4-enal, hexanal, 2-cyclobutylacetaldehyde.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
Processes for the preparation of the compounds of the general formula (I) according to the invention have additionally been found, characterized in that
[A] compounds of the general formula (II)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Mxe2x80x94Hxe2x80x83xe2x80x83(II)
in which
R1, A, D, E and G have the meaning indicated above and
M represents oxygen or xe2x80x94N(R32)xe2x80x94 and
R32 is hydrogen or (C1-C4)-alkyl,
are reacted with compounds of the general formula (III)
R33xe2x80x94Qxe2x80x94R2xe2x80x83xe2x80x83(III)
in which
R2 has the meaning indicated above,
R33 represents halogen, preferably chlorine or iodine,
Q represents a radical of the formula xe2x80x94SO2xe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94P(O)(OR27)xe2x80x94 or a single bond,
in which
R27 has the meaning indicated above,
to give compounds of the general formula (Ia)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Mxe2x80x94Qxe2x80x94R2xe2x80x83xe2x80x83(Ia)
in which
R1, A, D, E, G, M, Q and R2 have the meaning indicated above, in inert solvents, if appropriate in the presence of a base,
or
[B] compounds of the general formula (II) are reacted first with trialkylsilyl chlorosulphonates, preferably trimethylsilyl chlorosulphonates, treated with an acid and then reacted with a chlorinating agent, preferably phosphorus pentachloride, to give a compound of the general formula (IV)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Mxe2x80x94SO2xe2x80x94Clxe2x80x83xe2x80x83(IV)
in which
R1, A, D, E, G, and M have the meaning indicated above, and then reacted with compounds of the general formula (V)
Hxe2x80x94Txe2x80x94R2xe2x80x83xe2x80x83(V)
in which
R2 has the meaning indicated above, and
T represents oxygen or nitrogen,
to give compounds of the general formula (Ib)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Mxe2x80x94SO2xe2x80x94Txe2x80x94R2xe2x80x83xe2x80x83(Ib)
in which
R1, A, D, E, G, M, T and R2 have the meaning indicated above, in inert solvents in the presence of Bzlxe2x80x94NEt3+Clxe2x88x92 and a base,
or
[C] compounds of the general formula (VI)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Hxe2x80x83xe2x80x83(VI)
in which
R1 and A have the meaning indicated above and
Dxe2x80x2 represents oxygen, sulphur or xe2x80x94N(R9)xe2x80x94 and
R9 has the meaning indicated above,
are reacted with compounds of the general formula (VII)
R34xe2x80x94Exe2x80x94Gxe2x80x94SO2xe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83(VII)
in which
E, G and R2 have the meaning indicated above and
R34 represents a leaving group, preferably halogen, particularly preferably fluorine, chlorine or bromine,
to give compounds of the general formula (Ic)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Exe2x80x94Gxe2x80x94SO2xe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83(Ic)
in which
R1, A, Dxe2x80x2, E, G and R2 have the meaning indicated above,
or
[D] compounds of the general formula (Id)
R37xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94R2xe2x80x83xe2x80x83(Id)
in which
A, D, E, G, L and R2 have the meaning indicated above and
R37 represents a radical of the formula 
in which
R41 represents (C1-C6)-alkyl,
are reacted with a chloroformic acid ester, preferably 1-(1-chloro)ethyl chloroformate or methyl chloroformate, and then with alcohols, preferably methanol, if appropriate in the presence of a base, to give compounds of the general formula (Ie)
R38xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94R2xe2x80x83xe2x80x83(Ie)
in which
A, D, E, G, L and R2 have the meaning indicated above and
R38 represents a radical of the formula 
or
[E] compounds of the general formula (Ie) are reacted with (C1-C6)-ketones or (C1-C6)-aldehydes in the presence of a reducing agent, preferably sodium cyanoborohydride, if appropriate in the presence of an acid, to give compounds of the general formula (If)
R39xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94R2xe2x80x83xe2x80x83(If)
in which
A, D, E, G, L and R2 have the meaning indicated above and
R39 represents (C3-C6)-alkenyl or (C1-C6)-alkyl,
or
[F] compounds of the general formula (Ie) are reacted with compounds of the general formula (VIII)
R35xe2x80x94R3xe2x80x83xe2x80x83(VIII)
in which
R3 has the meaning indicated above,
R35 represents a leaving group, preferably halogen, in inert solvents, if appropriate in the presence of a base, to give compounds of the general formula (Ig)
R40xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94R2xe2x80x83xe2x80x83(Ig)
in which
A, D, E, G, L and R2 have the meaning indicated above and
R40 represents a radical of the formula 
in which
R3 has the meaning indicated above,
or
[G] compounds of the general formula (Ih) 
in which
A, D, E, G, L and R2 have the meaning indicated above, are converted by means of free-radical bromination, for example with N-bromosuccinimide, in an inert solvent into compounds of the general formula (Ii) 
in which
A, D, E, G, L and R2 have the meaning indicated above,
and then reacted with compounds of the general formula (IX) or (X) 
in which
R42 represents (C1-C6)-alkyl and
R3 has the meaning indicated above,
in inert solvents, if appropriate in the presence of a base, to give compounds of the general formula (Ij)
xe2x80x83R43xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94R2xe2x80x83xe2x80x83(Ij)
in which
A, D, E, G, L and R2 have the abovementioned meaning and 
in which
R42 and R3 have the abovementioned meaning,
and, if appropriate, the abovementioned substituents are introduced and derivatized according to customary methods,
and if D=xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, starting from the corresponding thioethers (D=S), an oxidation is carried out according to customary methods,
and in the case of the ammonium compounds, starting from the corresponding amines, an alkylation is carried out.
The processes according to the invention can be illustrated by way of example by the following reaction schemes: 
Suitable solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane is preferred.
In general, suitable bases are alkali metal hydrides or alkoxides, such as, for example, sodium hydride or potassium tert-butoxide, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or C1-C4-alkylamines, such as, for example, triethylamine. Triethylamine, sodium hydride, pyridine and/or dimethylaminopyridine are preferred.
Suitable bases are additionally customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen-carbonate, or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide. Potassium carbonate and sodium hydroxide are particularly preferred.
In one variant, the reaction is carried out in pyridine to which a catalytic amount of DMAP is added. If appropriate, toluene can additionally be added.
In general, the processes are carried out at normal pressure. However, it is also possible to carry out the processes at elevated pressure or at reduced pressure (e.g. in a range from 0.5 to 5 bar).
The present invention additionally relates to compounds of the general formula (II)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Mxe2x80x94Hxe2x80x83xe2x80x83(II)
in which
R1, A, D, E, G and M have the meanings indicated above.
Preferred compounds of the general formula (II) are those
in which
R1 represents naphth-1-yl, optionally substituted by (C1-C6)-alkyl substituted by hydroxyl, (C1-C6)-acylamino, amino or (C1-C6)-alkoxy, indan-4-yl, substituted by hydroxy(C1-C6)-alkyl,
a radical of the formula 
in which
R3 is (C1-C6)-alkyl,
E and A represent a bond,
D represents an oxygen atom,
G represents 1,3-phenylene, 1,4-phenylene or 2,5-pyridylene, each of which is optionally substituted by halogen,
L represents a radical of the formula xe2x80x94NHxe2x80x94SO2xe2x80x94 or xe2x80x94Oxe2x80x94SO2xe2x80x94,
R2 represents (C1-C6)-alkyl which is optionally substituted by chlorine, trifluoromethyl, by a radical of the formula xe2x80x94Oxe2x80x94CH2xe2x80x94CF3 or by phenyl or by pyridyl, which for their part can be substituted by bromine or chlorine, and
M represents oxygen or xe2x80x94N(R32)xe2x80x94,
in which R32 is hydrogen or (C1-C4)-alkyl.
The compounds of the general formula (II) can be prepared, for example, by a process in which
[A] compounds of the general formula (VI)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Hxe2x80x83xe2x80x83(VI)
in which
R1, A and Dxe2x80x2 have the meaning indicated above, are reacted with compounds of the general formula (XI)
R44xe2x80x94Exe2x80x94Gxe2x80x94NO2xe2x80x83xe2x80x83(XI)
in which
E and G have the meaning indicated above, and
R44 is a leaving group, preferably halogen,
in inert solvents, if appropriate in the presence of a base, and then reacted with customary reducing agents, preferably H2/Pd/C in an inert solvent or with hydrazine hydrate, Pd/C, if appropriate with simultaneous hydrogenation of (Cxe2x80x94C) multiple bonds, to give compounds of the general formula (IIa)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Exe2x80x94Gxe2x80x94NH2xe2x80x83xe2x80x83(IIa)
in which
R1, A, Dxe2x80x2, E and G have the meaning indicated above,
or
[B] compounds of the general formula (IIb)
xe2x80x83R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94NH2xe2x80x83xe2x80x83(IIb)
in which
R1, A, D, E and G have the meaning indicated in claim 1, are reacted with a nitrosating agent, preferably an aqueous solution of sulphuric acid and sodium nitrite, and with subsequent warming, preferably to 60 to 100xc2x0 C., to give compounds of the general formula (IIc)
R1xe2x80x94Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94OHxe2x80x83xe2x80x83(IIc)
in which
R1, A, D, E and G have the abovementioned meaning,
or
[C] compounds of the general formula (XII)
R1xe2x80x94R36xe2x80x83xe2x80x83(XII)
in which
R1 has the meaning indicated above and
R36 represents a leaving group, preferably halogen, particularly preferably bromine,
are reacted with compounds of the general formula (XIII)
HOxe2x80x94Gxe2x80x94Oxe2x80x94R45xe2x80x83xe2x80x83(XIII)
in which
G has the meaning indicated above and
R45 represents (C1-C6)-alkyl, preferably methyl,
in an inert solvent, preferably dimethylformamide or pyridine, if appropriate in the presence of a base, preferably potassium carbonate, and if appropriate in the presence of copper(I/II) salts, preferably copper(II) oxide or copper(I) iodide, in a temperature range from 0xc2x0 C. to 200xc2x0 C., preferably 80 to 150xc2x0 C. and normal pressure, to give compounds of the general formula (Ik)
R1xe2x80x94Oxe2x80x94Gxe2x80x94Oxe2x80x94R45xe2x80x83xe2x80x83(Ik)
in which
R1, G and R45 have the abovementioned meaning,
and are then reacted in the presence of an acid, preferably hydrobromic acid, to give compounds of the general formula (IId)
R1xe2x80x94Oxe2x80x94Gxe2x80x94OHxe2x80x83xe2x80x83(IId)
or
[D] compounds of the general formula (VI)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Hxe2x80x83xe2x80x83(VI)
in which
R1, A and Dxe2x80x2 have the meaning indicated above, are reacted with compounds of the general formula (XIV)
R46xe2x80x94Exe2x80x94Gxe2x80x2xe2x80x94R47xe2x80x83xe2x80x83(XIV)
in which
R46 has the meaning indicated for R36 and is identical to or different from this,
E has the abovementioned meaning,
Gxe2x80x2 represents a doubly bonded 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of sulphur, nitrogen and/or oxygen, which can optionally be substituted by one or more, identical or different substituents as defined for G as indicated above, and
R47 represents halogen, preferably chlorine or bromine, to give a compound of the general formula (XV)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Exe2x80x94Gxe2x80x2xe2x80x94R47xe2x80x83xe2x80x83(XV)
in which
R1, A, Dxe2x80x2, E, Gxe2x80x2 and R47 have the abovementioned meaning,
in inert solvents, if appropriate in the presence of a base, and are then transformed with potassium amide in liquid ammonia into the corresponding free amines of the general formula (IIe)
R1xe2x80x94Axe2x80x94Dxe2x80x2xe2x80x94Exe2x80x94Gxe2x80x2xe2x80x94NH2xe2x80x83xe2x80x83(IIe)
in which
R1, A, Dxe2x80x2, E and Gxe2x80x2 have the abovementioned meaning.
DOS (German Offenlegungsschrift) 1 942 264 describes the preparation of fluorinated alkanesulphonyl chlorides, U.S. Pat. No. 5,149,357, inter alia, the preparation of a 4,4,4-trifluorobutanesulphonamide, but without disclosing the preparation of the corresponding sulphonamide.
The fluorinated sulphonyl chlorides were prepared analogueously to DOS (German) 1 942 264.
The present invention likewise relates to compounds of the general formula (XV)
xe2x80x83R48xe2x80x94SO2xe2x80x94(CH2)hxe2x80x94Uxe2x80x94(CH2)ixe2x80x94CR49R50xe2x80x94CF2xe2x80x94R51xe2x80x83xe2x80x83(XV)
in which
R48 is a leaving group,
U is oxygen or a single bond,
R49 and R50 are identical or different and denote H, F, Cl or CF3,
R51 is H, F, Cl or Br,
h is a number 1 or 2 and
i is a number 0 or 1, with the exception of the compounds in which
U is a single bond,
R49 and R50 are identical and denote H or F and
R51 denotes F, and with the exception of the compounds in which
U is oxygen,
R49 or R50 denotes Cl and
i denotes 0.
The present invention additionally relates to compounds of the general formulae (XVI) and (XVII)
R48xe2x80x94SO2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CF3xe2x80x83xe2x80x83(XVI)
or
R48xe2x80x94SO2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CF2xe2x80x94CF3xe2x80x83xe2x80x83(XVII)
in which
R48 is a leaving group.
Compounds in which R48 is chlorine are preferred.
Suitable solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane is preferred.
In general, suitable bases are alkali metal hydrides or alkoxides, such as, for example, sodium hydride or potassium tert-butoxide, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or C1-C4-alkylamines, such as, for example, triethylamine. Sodium hydride, pyridine and/or dimethylaminopyridine are preferred.
Suitable bases are additionally the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium hydrogen-carbonate, or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide Potassium carbonate and sodium hydroxide are particularly preferred.
The bases are employed in an amount from 1-20 equivalents, preferably from 2 to 10 equivalents, in each case based on 1 equivalent of the compounds of the general formulae (X) and (XII)
The processes are in general carried out at normal pressure However, it is also possible to carry out the processes at elevated pressure or at reduced pressure (e.g. in a range from 0.5 to 5 bar)
The processes are in general carried out in a temperature range from 0xc2x0 C. to 200xc2x0, preferably from room temperature to 140xc2x0 C.
The compounds of the general formulae (III), (V), (VIII), (IX), (X) and (XII) are known per se or can be prepared by customary methods.
Alkylation for the preparation of the ammonium compounds is in general carried out using alkylating agents such as, for example, alkyl halides, sulphonic acid esters or substituted or unsubstituted dialkyl or diaryl sulphates, preferably using methyl iodide or dimethyl sulphate.
Alkylation is in general carried out in one of the abovementioned solvents, preferably in dimethylformamide in a temperature range from 0xc2x0 C. to +70xc2x0 C., preferably from 0xc2x0 C. to +30xc2x0 C. and normal pressure.
Surprisingly, the new aryl sulphonamides and their analogues show an unforeseeable, useful spectrum of pharmacological action.
They are distinguished as highly effective agonists of the CB1 receptor and in some cases of the CB2 receptor. They can be employed alone or in combination with other medicaments for the treatment and/or prevention of neuronal damage of varying cause, such as, for example, due to ischaemic, thrombic and/or thromboembolic, and haemorrhagic stroke, and conditions after direct and indirect injuries in the area of the brain and of the skull, furthermore for the treatment and/or prevention of cerebral ischaemia after all operative interventions in the brain or peripheral organs or body parts and conditions of pathogenic or allergic nature accompanying or preceding them, which can lead primarily and/or secondarily to neuronal damage. Likewise, the compounds according to the invention are also suitable for the therapy of primary and/or secondary pathogenic conditions of the brain, for example during or after cerebral vasospasms, hypoxia and/or anoxia of previously unmentioned origin, perinatal asphyxia, autoimmune disorders, metabolic and organ disorders which can be accompanied by damage to the brain and also damage to the brain as a result of primary brain disorders, for example convulsive conditions and athero- and/or arteriosclerotic changes, for the treatment of chronic or psychiatric conditions such as, for example, depression, neurodegenerative disorders such as, for example, Alzheimer""s, Parkinson""s or Huntington""s disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and/or chronic viral or bacterial infections and multiinfarct dementia.
They can moreover be employed in medicaments for the treatment of states of pain, emesis, nausea, glaucoma, asthma, anorexia, convulsions, rheumatism, sedation and mobility disorders.
The substances according to the invention are also suitable for the treatment of disorders which are caused by bacterial and/or viral infections which are based on direct and/or indirect alterations of the immune system or on dysregulations with participation of the immune system, such as, for example, in local or systemic autoimmune diseases (e.g. lupus erythematosus in all its variants), inflammatory and/or autoimmunologically related diseases of the joints (e.g. primary chronic polyarthritis, trauma-related inflammation), inflammatory and/or autoimmunologically related diseases of the bone and muscle apparatus, inflammatory and/or autoimmunologically related pathogenic processes of the internal organs (e.g. Crohn""s disease, glomerulonephritis) and of the external organs (e.g. allergic reactions due to aerogenic intake of antigens) and of the central nervous system (e.g. multiple sclerosis, Alzheimer""s disease, psychiatric disorders) as well as of the sense organs, primary and/or secondary and/or autoimmunological disorders of the haematogenic system and of the immune system (e.g. rejection reactions, AIDS) themselves, and also in skin disorders of inflammatory and/or immunological origin in humans and animals These substances furthermore act on the indirect symptoms of these disorders such as, for example, pain.
Their use for the treatment of cerebral ischaemias and craniocerebral trauma is preferred.
1. Cloning of the Rat Cannabinoid Receptor CB1
Total RNA from rat brain (the tissue was taken from freshly killed animals and shock-frozen in liquid nitrogen) was isolated by acidic guanidinium thiocyanate/phenol/chloroform extraction (J. Biol. Chem. 1979, 18, 5294) and converted into cDNA by means of reverse transcriptase and random primers (in each case from Invitrogen). The polymerase chain reaction (PCR, conditions: 4 min 94xc2x0 C., 1xc3x97; 1 min 94xc2x0 C.; 2 min 53xc2x0 C.; 1 min 72xc2x0 C., 50 cycles; 1 min 94xc2x0 C., 2 min 53xc2x0 C., 4 min 72xc2x0 C., 1xc3x97) was carried out in a Perkin Elmer thermocycler using the enzyme Taq polymerase (Perkin Elmer); the oligonucleotide primers employed (bases 99 to 122: 5xe2x80x2xe2x86x923xe2x80x2, xe2x80x9cdownxe2x80x9d; 1556-1575: 3xe2x80x2←5xe2x80x2, xe2x80x9cupxe2x80x9d) were derived from the published sequence of the rat cannabinoid receptor (Nature 1990, 346, 561) and were synthesized on a DNA synthesizer, model 1380 from Applied Biosystems. One part of the PCR reaction was separated in a 1% strength agarose gel in 1xc3x97 TBE buffer and then stained with ethidium bromide, only one band having the expected length being visible (approximately 1.5 kb). This PCR product was subcloned into the TA cloning vector (Invitrogen) and the nucleotide sequence of the inserts was determined by the dideoxynucleotide chain termination reaction using T7DNA polymerase (Sequenase, USA/Amersham). The insert has a length of 1477 base pairs and contains an open reading frame of 1419 base pairs which corresponds to a protein of 473 amino acids. The number of base pairs, the position of the open reading frame and the number of amino acids agree with the published sequence. Computer analyses were carried out with the aid of the GCG software suite (Genetic Computer Group). The cDNA insert was subcloned into the expression vector pRc/CMV after partial digestion with HindIII and NotI (Biolabs). This construct (plasmid CMV-RH) was employed for transfection experiments.
2. Stable Transfection of the CHOluc9 Reporter Cells
CHOluc9 cells were cultured in 50% Dulbecco""s modified Eagle medium/50% F-12 (DMEM/F12) which contained 10% foetal calf serum (FCS). Transfections were prepared in 6-well plates. 7.5 xcexcg of Qiagen-purified CMV-RH plasmid DNA were added per 105 cells with the DOTAP transfection system, corresponding to the experimental protocol of the manufacturer (Boehringer Mannheim). Transfected cells were selected using 1 mg/ml G418 and individual clones were obtained by limiting dilution in 96-well plates. Cell lines which express the cannabinoid receptor were identified for the inhibition of reporter gene expression after incubation with the cannabinoid receptor agonist, WIN-55,212-2, in the presence of forskolin. Several stable transfected and subcloned cell lines were further characterized by means of RT-PCR, as described under 1.
3. Test Optimization and Pharmacological Characterization of the CHOCB1 Reporter Cell Line
With the aim of high sensitivity and reproducibility, low variance and high suitability for carrying out on the robotic system, the luciferase test was optimized by variation of several test parameters, such as, for example, cell density, duration of the growth phase and the test incubation, forskolin concentration, medium composition. The following test protocol was used for pharmacological characterization of the cells and for robot-assisted substance screening: the stock cultures were cultured in 50% Dulbecco""s modified Eagle medium/50% F-12 (DMEM/F12) with 10% FCS at 37xc2x0 C. under 10% CO2 and in each case split 1:10 after 2 to 3 days. Test cultures were inoculated into 96-well plates at 5000 cells per well and cultured at 37xc2x0 C. for 70 hours. The cultures were then carefully washed with phosphate-buffered saline and reconstituted using serum-free ultra-CHO medium (Bio-Whittaker). The substances dissolved in DMSO were diluted 1xc3x97 in medium and pipetted into the test cultures (maximum DMSO final concentration in the test batch: 0.5%). 20 minutes later, forskolin was added and the cultures were then incubated at 37xc2x0 C. in an incubator for 3 hours. The supernatants were then removed and the cells were lysed by addition of 25 xcexcl of lysis reagent (25 mM triphosphate, pH 7.8 with 2 mM DTT, 10% glycerol, 3% Triton X100) Directly after this, luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mM MgSO4, 15 mM DTT, pH 7.8) was added, the mixture was briefly shaken and the luciferase activity was measured using a Hamamatzu camera system
For inactivation of Gi proteins, the test cultures were treated with 5 mg/ml (final conc.) of Pertussis toxin for 16 hours before the test
The IC50 values were calculated using the GraphPadPrism(trademark) program (Hill equation, specific: one-site competition).
Activity in the rat CB1 receptor luciferase receptor gene test
CHOluc9 cells were stably transfected using the human CB2 receptor. Transfection, clone selection and test development were carried out analogueously to the studies using the rat CB1 receptor. The following test protocol was used for the pharmacological characterization of the cells and for substance testing:
The stock cultures were cultured in 50% Dulbecco""s modified Eagle medium/50% F-12 (DMEM/F12) with 10% FCS at 37xc2x0 C. under 10% CO2 and in each case split 1:10 after 2 to 3 days. Test cultures were inoculated into 96-well plates at 5000 cells per well in DMEM/F12 medium with 5% FCS and cultured at 37xc2x0 C. for 70 hours The medium was then removed from the cultures and replaced by serum-free ultra-CHO medium (Bio-Whittaker). The substances dissolved in DMSO (200xc3x97 final concentration) were pipetted into the test cultures (maximum DMSO final conc. in the test mixture 0.5%) and 20 min later forskolin was added The cultures were then incubated at 37xc2x0 C. in an incubator for 3.5 hours The supernatants were then removed and the cells were lysed by addition of 25 xcexcl of lysis reagent (25 mM triphosphate, pH 7.8 with 2 mM DTT, 10% glycerol, 3% Triton X100). Directly following, 50 xcexcl of luciferase substrate solution, double-concentrated (5 mM ATP, 1 mM luciferin, 0.2 mM coenzyme A, 10 mM tricine, 1.35 mM MgSO4, 15 mM DTT, pH 7.8) were added, the mixture was briefly shaken, and the luciferase activity was determined using a photomultiplier camera measuring system (Hamamatzu)
The IC50 values were calculated using the GraphPadPrism(trademark) program (Hill equation; specific one-site competition).
Membrane protein is prepared from different tissues or from cells by standard methods. Buffer, labelled ligand, DMSO or test substance are pipetted together, then 100 xcexcg of protein are added, and the mixture is well mixed and incubated in a water bath at 30xc2x0 C. for 60 min. After expiry of the incubation time, the reaction is stopped by addition of ice-cold incubation buffer to each tube. After filtering off, washing is carried out with xc2xe ml of incubation buffer. The filters are transferred to minivials and the radioactivity is determined in a scintillation counter. Affinity for the CB1 receptor (rat cortex membranes)
After decapitation of a rat, the skull is opened, and the brain is lifted out and cut along the median fissure. The hippocampus is exposed, separated from the remaining tissue, cut into 350 xcexcm thick sections and incubated at 37xc2x0 C. in straining vessels for 60 min Followed by basal value and stimulation 1 with 75 mM KCl (S1), the sections are incubated with test substance and then stimulation is repeated with KCl and test substance (S2). Glutamate concentration of the samples to be investigated is then measured by means of an enzymatic action (GLDH) and fluorometric measurement of NADH. By means of a calibration curve, the glutamate content of the sample is determined, and with knowledge of the protein content the glutamate content/mg of protein can be calculated The ratio S2/S1 is compared; glutamate release inhibitors reduce this ratio in a concentration-dependent manner.
1. Agonism Testing:
Five minutes after determination of the basal body temperature via an oesophageal temperature probe, the test substance is administered (i.v.). A control group receives only the solvent for the test substances, likewise i.v. The body temperature is measured 7.5, 15, 30 and 60 minutes after i.v. administration. The group size per dose is 5-7 animals (rats).
Rat hypothermiaxe2x80x94Agonism testing
2. Antagonism Testing:
The specific CB1 antagonist SR 141716A or, to the control group, only the solvent (Solutol/0.9% NaCl), is administered intraperitoneally 60 minutes before administration of test substance. The basal body temperature is measured five minutes before administration of SR 141716A via oesophageal temperature probe The further procedure corresponds to the xe2x80x9cagonism testingxe2x80x9d method The group size per dose is 5-7 animals (rats).
Under isoflurane anaesthesia, the median cerebral artery is exposed on one side and the latter and its side branches are irreversibly sealed by means of electrocoagulation. As a result of the intervention a cerebral infarct is formed. During the operation, the body temperature of the animal is kept at 37xc2x0 C. After wound closure and wearing off of the anaesthesia, the animals are again released into their cage. The administration of substance is carried out according to different time schemes and via different administration routes (i.v., i.p.) after occlusion. The infarct size is determined after 7 days. To do this, the brain is removed, worked up histologically and the infarct volume is determined with the aid of a computer-assisted analysis system.
Activity in the model of permanent focal cerebral ischaemia (MCA-O)
Under anaesthesia, the animal""s own blood is injected subdurally on one side An infarct is formed under the haematoma. Substance administration is carried out according to different time schemes and via different administration routes (i.v., i.p.) The determination of the infarct size is carried out as described in the model of permanent focal ischaemia in the rat (MCA-O)
Activity in the model xe2x80x9csubdural haematoma in the rat (SDH)xe2x80x9d
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compound using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if water is used as a diluent.
Administration is carried out in a customary manner, preferably orally, transdermally or parenterally, in particular perlingually or intravenously.
In general, it has proved advantageous in the case of intravenous administration to administer amounts from approximately 0.01 to 10 mg/kg, preferably approximately 0.1 to 10 mg/kg, of body weight to achieve effective results.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.